tbuckley/cabot-search huggingface dataset:
Overall survival (OS) in metastatic uveal melanoma: A summary of recent prospective trials.
Authors: Josep M. Piulats, Alexander Noor Shoushtari, Sebastian Ochsenreither, Shaad Essa Abdullah, Chris Holland, Michelle L. McCully, Jean-Francois Baurain
Journal: Journal of Clinical Oncology (2022)

e21598 Background: Metastatic uveal melanoma (mUM) historically has a poor prognosis where chemotherapy and checkpoint blockade, including combination, has had no impact on OS. Tebentafusp (tebe), a TCR bispecific (gp100 x CD3), is the first therapy to demonstrate an OS benefit in a mUM randomized trial (IMCgp100-202) against pembrolizumab (pembro), ipilimumab (ipi) or dacarbazine. Here we present a summary of OS from recent prospective trials in mUM in both previously untreated (1L) and previously treated (2L+) mUM including cross trial comparison with checkpoint blockade combination. Methods: A literature review of prospective Ph2/3 clinical trials of systemic therapies in mUM published recently (2019-2021) identified 8 trials: in 1L mUM (n = 2) a randomized Ph3 of tebe (N = 252) vs investigator’s choice (IC; N = 126) of pembro, ipi or dacarbazine (IMCgp100-202) and a single arm Ph2 of nivolumab (nivo) + ipi (N = 52; Piulats, 2021) (Table); in 2L+ mUM (n = 1) a single arm Ph2 of tebe (N = 127; IMCgp100-102); and in mixed line mUM (n = 5) a randomized Ph2 of cabozantinib (N = 31) vs chemotherapy (N = 15; Luke, 2019), a single arm Ph2 of nivo + ipi (N = 35; Pelster, 2021), a single arm Ph2 of pembro + entinostat (N = 29; Ny, 2021), a single arm Ph2 of glembatumumab (N = 37; Hasanov, 2020), and a single arm Ph2 of IMC-A12 (IGF-1 receptor inhibitor; N = 18; Mattei, 2020). The PUMMA (Khoja, 2019; N = 912) and Rantala, 2019 (N = 2494; n = 510 1L pts) meta-analyses were included to provide historical benchmarks for OS. Results: In previously untreated mUM, 1-yr and median OS were 73% and 21.7 months for tebe, 59% and 15.7 months for pembro, 52% and 12.7 months for nivo + ipi and 45% and 11.3 months for conventional chemotherapy. In previously treated mUM, 1-yr and median OS were 61% and 16.8 months for tebe, 34% and 7.0 months for checkpoint inhibitors, and 43% and 10.5 months for conventional chemotherapy. In mixed line (1L+) mUM, 1-yr and median OS were 56% and 19.1 months for nivo + ipi and 59% and 13.4 months for pembro + entinostat, 13.8 months for IMC-A12, 11.9 months for glembatumumab and 6.4 months for cabozantinib. Related AEs (any grade) leading to discontinuation and death for tebe were 2% and 0% vs 5% and 0% for IC control, and 23% and 3.8% for nivo + ipi in 1L pts. Conclusions: Tebe is the only therapy demonstrated to prolong OS in mUM. The 1-yr OS for tebe in 1L and 2L+ is superior to all recent published studies, including nivo + ipi. Both tebe and checkpoint combination therapy have high rate of any grade AEs, although checkpoint combination has a higher rate of treatment related discontinuations and deaths.[Table: see text]
Anlotinib suppresses growth and metastasis through MAPK signaling pathway in cisplatin-resistant ovarian cancer cells.
Authors: Yurou Ji, Pengpeng Qu
Journal: Journal of Clinical Oncology (2022)

e17542 Background: Anlotinib is a highly potent multi-target tyrosine kinase inhibitor. Increasing evidence suggests that anlotinib exhibits effective anti-tumor activity in various cancer types. However, the functional roles of anlotinib on cisplatin-resistant ovarian cancer are yet to be elucidated. The objective of this study was to investigate the anti-tumor effects of anlotinib in the pathogenesis of cisplatin-resistant ovarian cancer cells and tried to explore the related molecular mechanisms. Methods: Human ovarian cancer cells (A2780 and A2780 CIS) were cultured and treated with or without anlotinib. The effects of anlotinib on cells proliferation were determined by CCK-8 assay and colony formation assay. To evaluate the invasion and metastasis of ovarian cancer cells, we conducted wound healing and trans-well assay. Cell cycle was detected by flow cytometry. Moreover, the xenograft mouse model was used for conducting in vivo studies to verify the effect of anlotinib. The expression of Ki-67 in the tumor tissue was detected by immunohistochemistry. In GSE15372, differential expressed genes (DEGs) between cisplatin-sensitive and cisplatin-resistant groups were analyzed and enriched pathways were identified. Real-time qPCR and Western blot were used to measure the mRNA or protein level. Results: In vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration, and invasion restraint. Meanwhile, xenograft cisplatin-resistant ovarian tumor models revealed that anlotinib treatment dramatically hindered in vivo tumor cells growth. HE and Ki-67 staining showed anlotinib markedly inhibited cisplatin-resistant ovarian cancer cells proliferation. Polo-like kinase 2 (Plk2) was identified as the main target gene of cisplatin-resistant ovarian cancer cells through bioinformatics analysis. Furthermore, we found that anlotinib upregulated the expression of Plk2 and suppressed the MAPK signaling pathway activation. The high expression of Plk2 might serve as a promising indicator when used to predict a favorable therapeutic response. Conclusions: In this study, we found that anlotinib had excellent anti-tumor effects in cisplatin-resistant ovarian cancer cells both in vitro and in vivo. These present results add to the growing body of evidence supporting anlotinib as a potential anti-cancer agent in ovarian cancer.
Genomic characteristics of homologous recombination deficiency in ovarian cancer.
Authors: Xiaoxue Ma, Mingwei Li, Feng Lou, Shanbo Cao, Huina Wang
Journal: Journal of Clinical Oncology (2022)

e17575 Background: HRD score correlates with sensitivity to PARP inhibitors (PARPi). BRCA1/2 mutations are well-known causes of HRD, but other genetic abnormalities of the homologous recombination repair (HRR) pathway could also cause HRD, although no consensus has been reached. We aimed to analyze HRD score and its relationship with genetic characteristics in ovarian cancer, particularly the HRR-related genes mutations. Methods: Matched tumor/normal DNA from Chinese patients with ovarian cancer (N = 181) were analyzed by Acornmed panel with 98 cancer-related genes. The HRD score is the sum of these scar signature scores, namely, the loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). HRR genes mutations and clinical outcomes from the TCGA cohort were included. Results: In our cohort, 44.2% patients exhibited HRR genes mutations, yielded an increment of 12.2% than BRCA mutants. The most frequently mutated HRR genes were BRCA1 (25.0%), BRCA2 (8.0%), CDK12 (4.0%), and RAD51D (4.0%). Chinese cohort contained frequently somatic mutation of HRR genes compared with TCGA cohort (22.7% vs 13.6%, p &lt; 0.010). Germline mutations of HRR genes and non-HRR genes occurred in 21.5% and 2.8% of cases detected, respectively. HRD score in HRR-related genes wildtype was lower than tumors with BRCA1/2 mutation and HRR genes mutation without BRCA1/2 carriers (median HRD score 33, 72 and 64; p &lt; 0.001). Interestingly, no difference was observed in HRD scores between patients with somatic BRCA-mut and germline- BRCA mutants. The median HRD score in our cohort was 65 (range from 0 to 96), and 58.6% patients were HRD-high with the cutoff of HRD score ≥ 42. The HRD-high patients covered 89.7% of the BRCA-positive cases, besides, approximately 77.3% of the BRCA-wt/HRR-mut patients also harbored high HRD scores. Six mutated genes were significantly different between HRD-high and HRD-low group. ARID1A was frequently mutated in patients with HRD-low, while significantly more mutations in TP53 were identified among HRD-high patients. Interestingly, in the TCGA cohort, patients with TP53-mut (p = 0.024) and individuals without ARID1A mutation (p &lt; 0.001) had remarkably high survival rates, as compared with the rest of these patients.Furthermore, tumors with HRD-high had a bit higher TMB (median TMB 4.56 vs 2.91, p = 0.018). Conclusions: Our data suggest that HRR genes mutations strongly affect HRD score, which may increase the number of patients who may benefit from PARPi treatment, and combining gene mutations and HRD score could optimize prognosis stratification in ovarian cancer. In addition, the molecular features of HRD provide new opportunities to predict the tumor response to multiple treatments.
Oscillatory shear stress augments endothelial pannexin1 by inhibiting macro-autophagy
Authors: F Molica, A Hautefort, T Idris, G Pelli, B Foglia, BR Kwak
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Atherosclerotic lesions preferentially develop in arterial regions exposed to disturbed blood flow, which are characterized by a dysfunctional proinflammatory endothelial cell (EC) phenotype. ECs release ATP in response to changes in wall shear stress (WSS), which subsequently regulates the inflammatory response. ATP can be released from cells in a controlled manner through Pannexin1 (Panx1) channels. Objective To study the expression of Panx1 in response to WSS and its role in the endothelium. Methods Human ECs (HUVECs or EA.hy926) were exposed to physiological high laminar shear stress (HLSS) and atheroprone oscillatory shear stress (OSS) for 48h using an orbital shaker. Panx1 transcript and protein levels were determined by qPCR and Western blot, respectively. mRNA was extracted for RNAseq. WSS-modifying casts were placed for 1 week around the carotid artery of mice and Panx1 expression was analyzed en face. Carotid WSS-modifying casts were also placed in Tie2CreTgPanx1fl/flApoE-/- and Panx1fl/flApoE-/- mice followed by 9 weeks high fat diet. CD68+ cells were quantified in OSS-induced atherosclerotic lesions. Results We found that Panx1 expression was increased in carotid regions exposed to OSS as compared to HLSS regions. These results were confirmed in vitro in HUVECs. In silico analysis of the promotor of Panx1 revealed binding sites for the WSS-sensitive transcription factors NF-kB and CREB. NF-kB and CREB mRNA levels were similar under OSS and HLSS, however NF-kB activation (phospho-NF-kB) was detected in ECs under OSS. Surprisingly, Panx1 mRNA level was not affected under these conditions, suggesting that the increased Panx1 protein observed under OSS may be due to decreased Panx1 degradation rather than to increased synthesis of the protein. Unbiased analysis of differential gene expression in ECs exposed to HLSS or OSS revealed 320 up-regulated and 353 down-regulated genes under OSS. Down-regulated genes included proteins involved in macro-autophagy. Inhibition of macro-autophagy in ECs by exposure to chloroquine for 6h increased the expression of glycosylated Panx1, suggestive for more Panx1 channels at the plasma membrane under these conditions. Finally, we observed that atherosclerotic lesions in OSS regions of Tie2CreTgPanx1fl/flApoE-/- mice contained more CD68+ cells than Panx1fl/flApoE-/- controls. Conclusion Endothelial Panx1 expression is upregulated in response to OSS. Absence of OSS effects on NF-kB, CREB and Panx1 mRNA revealed that the upregulation of Panx1 protein is not due to transcriptional effects of OSS. Expression of genes involved in the macro-autophagic process were down-regulated under OSS, and chemical inhibition of macro-autophagy augmented the plasma membranous form of Panx1. OSS-induced decrease in autophagic flux may enhance ATP release through Panx1 channels, thereby counterbalancing leukocyte recruitment in atherosclerosis.
Bedside to benchtop translational development: Targeting the S1P/ceramide axis may alleviate symptoms of chemical induced peripheral neuropathy.
Authors: Ray Takigiku, Robert Wesolowski, Olivier Rixe, John Charles Morris, Emrullah Yilmaz, John L. Villano, Carolyn Muller, Richard Charles Curry, Vinay K. Puduvalli, Trisha Michel Wise-Draper, Darren Wolfe, Gilles Tapolsky
Journal: Journal of Clinical Oncology (2022)

e15045 Background: Chemical Induced Peripheral Neuropathy (CIPN) is a debilitating and serious side-effect associated with many chemotherapeutic treatments. Often, CIPN is a dose-limiting toxicity, and its effects can be long-lasting in some patients. The pathology of CIPN is thought to involve not only cytotoxicity of neuronal cells, but also inflammation and immune responses. Hence, it is not surprising that the sphingolipid sphingosine-1-phosphate (S1P) is thought to be a key contributor to CIPN. Methods: BXQ-350, a nanovesicle comprised of recombinantly expressed Saposin C and dioleoylphosphatidylserine, has broad anticancer activity. It modulates sphingolipid metabolism and signaling, lowers S1P and increases pro-apoptotic ceramides, and induces an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 )*. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetics, efficacy profile and to elucidate potential biomarkers. Results: Interestingly, several patients with established CIPN spontaneously reported improvement of their neuropathy-related symptoms following BXQ-350 administration. Plasma samples from those patients revealed changes in circulating levels of sphingolipids and cytokines, including reduction of circulating levels of S1P and of IL-6, IL-8, cytokines, following BXQ-350 dosing. These properties of BXQ-350 were subsequently investigated in a murine oxaliplatin-CIPN preclinical model; results showed a dose-dependent prevention/resolution of CIPN, which also correlated with decreasing systemic S1P levels. Additional plasma based CIPN specific biomarkers were investigated, and preclinical results suggest that BXQ-350 may also favorably inhibit specific immune cells that favor CPIN. Conclusions: These preclinical and clinical observations related to CIPN, coupled with the fact that BXQ-350 acts synergistically with many chemotherapies and radiation, warrant further its investigation into preventing or improving CIPN related symptoms in cancer patients. Clinical trial information: 02859857.
Clinical utility of circulating tumor DNA in patients with head and neck cancers.
Authors: Mykola Onyshchenko, Adam Rock, Chad Sila, Katie LaBarbera, Richa Rathore, Ping Ji, Laron McPhaul
Journal: Journal of Clinical Oncology (2022)

e18003 Background: Globally, head and neck cancers (HNCs) account for over 900,000 cases annually with a meager overall survival rate of 50%. While early-stage HNCs may be amenable to surgery, advanced disease is treated with systemic therapy or chemoradiation. For localized disease, chemo-radiation is often curative, but is associated with severe toxicity. Assessment of systemic treatment in the era of immunotherapy is often challenging due to the pseudoprogression phenomenon. In general, surveillance is limited to clinical follow-up and radiological imaging due to the lack of a sensitive and specific biomarker to assess treatment response and disease progression. Circulating tumor DNA (ctDNA) has shown promise as a reliable marker of disease activity in several solid tumors. In this study we evaluated the clinical utility of ctDNA for monitoring of therapeutic response and disease progression in patients with HNCs. Methods: ctDNA analysis was performed utilizing a personalized, tumor-informed ctDNA assay (Signatera™ bespoke mPCR NGS assay) in patients with advanced stage (III, IV) HNC who underwent chemoradiation or systemic therapy. ctDNA levels were measured at diagnosis, throughout treatment and during remission. The primary endpoint was correlation of ctDNA kinetics with radiological response. The secondary endpoint was the rate of ctDNA positivity during remission. Additional data collected included patient demographics and tumor clinicopathologic characteristics. Analysis was conducted using descriptive statistics. Results: ctDNA kinetics from 15 patients with squamous HNCs were analyzed. Due to insufficient time points, 5 five patients were excluded from this analysis. At diagnosis, 9/10 (90%) patients were ctDNA-positive, with baseline ctDNA levels ranging from 0.2 to 8500 mean tumor molecules (MTM)/mL of plasma. Patients received either chemoradiation (7/10) or (chemo)immunotherapy (3/10). Among patients who received chemoradiation, 4 out of 7 cleared ctDNA in less than 40 days, while 2 out of 7 had persistent ctDNA after 40 days. Those who showed ctDNA clearance had a continued response at 3-6 month follow-up both by ctDNA and by standard of care imaging. The 2 patients that did not clear ctDNA by day 40 ultimately relapsed on imaging and had rising ctDNA levels within 3 months of completion of chemoradiation. The patient who was ctDNA negative at baseline remained negative throughout the treatment and follow up. Of the patients who received chemo(immunotherapy), 2/3 cleared ctDNA after 2 cycles of therapy and continued to be in remission. The remaining patient who did not show ctDNA clearance became refractory to treatment. Conclusions: Our study demonstrates the feasibility of personalized and tumor-informed ctDNA in patients with advanced HNCs. Monitoring of ctDNA kinetics during therapy may enable prediction of therapeutic response and early disease progression to guide clinical decision-making.
HERibuline: Eribulin mesylate and Trastuzumab in pretreated HER2-positive advanced breast cancer—A report of region’s practice.
Authors: Noemie Gassian, Sophie Paget-Bailly, Oum El Kheir Djoumakh, Laura Mansi, Erion Dobi, Fernando Bazan, Elsa Curtit, Loic Chaigneau, Nathalie Meneveau, Marie-Justine Paillard, Zohair Selmani, Julien Viot, Christophe Borg, Guillaume Meynard
Journal: Journal of Clinical Oncology (2022)

e13020 Background: Until 2020, in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), the two first lines of metastatic treatment were well defined but after, many options were possible, most often combining targeted therapy plus chemotherapy. Eribulin mesylate is indicated for the treatment of patients with ABC previously treated by anthracycline and taxane regimens in the advanced setting. Here, we present the results of eribuline and trastuzumab (E/T) combination in HER2-positive ABC previously treated. Methods: Patients with HER2-positive ABC treated with the E/T combination from our region cancer institute were included in this retrospective study. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and safety. Results: Between November 2013 and July 2019, a total of 34 consecutive patients with HER2-positive ABC were included. The median number of previous lines for advanced setting was 4 (range 2-7). Patients treated by taxanes and anthracyclines represented 91% and 47% respectively; 50%, 79% and 62% were previously treated with pertuzumab, trastuzumab emtansine and lapatinib respectively. After a median follow up of 24.8 months, median PFS was 6.2 months (95% CI [3.35-7.13]) and median OS was 12.6 months (95% CI [7.13-18.56]). The ORR and CBR were 38% and 53%, respectively. No unexpected adverse event was observed. The most frequent grade 3-4 toxicity was hematologic (44.1%). Conclusions: Recently, new therapies have revolutionized the management of HER2-positive ABC and patients benefit from a prolonged overall survival associated with a maintained performance status. However, in pretreated and advanced metastatic setting, there are few scientific evidence to guide the choice of treatments. A combination of E/T could be an effective option in patients with good performance status and willing to receive treatment.
The Future of Telemedicine in Oncology
Authors: Lucy R. Langer, Amye J. Tevaarwerk, Robin Zon, Travis Osterman
Journal: Journal of the National Comprehensive Cancer Network (2022)

Abstract The COVID-19 pandemic has led to a massive surge in the use of telemedicine services in oncology. However, although telemedicine usage is not as high as it was early in the pandemic, it is not as low as it was before the pandemic, either, indicating that patients have a desire to receive care when, where, and how they want. Most oncology providers agree that telemedicine is beneficial and here to stay, but barriers hinder equitable delivery, such as racial/ethnic affiliations, older age, residing in a rural area, and lower socioeconomic status. The momentum created by the pandemic can serve to show the benefits of telemedicine and solidify its place in oncology care. However, addressing these disparities—and increasing widespread access to broadband and educating both patients and providers on how to use these technologies—is paramount.
Prediction of pathologic complete response to neoadjuvant chemotherapy in breast cancer (SWOG S0800) using image analysis-based tumor infiltrating lymphocyte measurements.
Authors: Kim Blenman, Kristina Fanucci, Yalai Bai, Vasiliki Pelekanou, Zeina A. Nahleh, Saba Shafi, Sneha Burela, William E. Barlow, Priyanka Sharma, Alastair Mark Thompson, Andrew K. Godwin, David L. Rimm, Gabriel N. Hortobagyi, Lajos Pusztai
Journal: Journal of Clinical Oncology (2022)

594 Background: Image analysis-based tumor infiltrating lymphocyte (TIL) quantitation methods are being developed to eliminate reader-to-reader variation in TIL assessment that hinders its clinical adoption as prognostic and chemotherapy response predictive marker. We evaluated the ability of an image analysis-based TIL score to predict pathologic complete response (pCR) and event free survival (EFS) in breast cancer. Methods: 113 pretreatment samples were analyzed from the SWOG S0800 trial that randomized stage IIB-IIIC HER-2-negative breast cancers to neoadjuvant chemotherapy with or without bevacizumab. TIL quantitation was performed on H&amp;E sections using QuPath open-source software and a convolutional neural network cell classifier (CNN11). The digital easTILs% score was calculated as [sum of TIL Area (mm 2 ) / Stromal Area (mm 2 )] x 100. Pathologist-read stromal TIL score (sTILs%) was defined using international guidelines. A previously validated threshold of easTILs% &gt; 19.9% defined high easTILs% status. Results: Pretreatment easTILs% was significantly higher in cases with pCR compared to residual disease (RD) (means, 31% vs. 17%, p &lt; 0.001). easTILs% high and low cases had pCR rates of 41% and 21% (p = 0.019), respectively. In logistic regression adjusting for other factors, easTILs% was prognostic for pCR as continuous score (p &lt; 0.001) and as high vs low categories (p = 0.035). There was strong positive correlation between easTILs% and sTILs% (r = 0.606, p &lt; 0.0001), and sTILs% was also predictive of pCR. The areas under the prediction curve (AUC) were 0.709 and 0.627 for easTILs% and sTILs%, respectively. There was no statistically significant interaction between easTILs% and bevacizumab benefit (p = 0.26), and higher easTILs% or sTILs were not associated with better EFS. Conclusions: Image analysis-based TIL quantification is predictive of pCR in breast cancer and had better pCR outcome discrimination than pathologist-read sTIL count. [Table: see text]